Pertussis in young infants can progress to complicated and severe disease (critical pertussis), often requiring hospitalization and still causing an alarming number of deaths. Recent pertussis epidemics increase the likelihood of exposure of young infants to the infection, which is especially dangerous to pre-vaccination infants (<2 mo old). However, no effective therapies exist for treatment of critical pertussis. Pertussis toxin (PT), a major virulence factor of Bordetella pertussis, inhibits G protein signalin and causes dramatic leukocytosis in infected infants, a morbidity that correlates with poor outcome. We hypothesize that PT plays a major role in the pathogenesis of critical pertussis disease through multiple effects on infection and host responses. Our preliminary data demonstrate that PT promotes lethality of pertussis infection in infant mice, but also reveal that pertussis infection and disease in infant mice have characteristics quite different from those in adult mice. This reflects pertussis disease in humans, where infants are susceptible to severe disease and death, but older children and adults suffer less severe disease and no deaths. We propose to study the role of PT in exacerbation of pertussis infection and disease in infant mice. A host target of PT that may provide therapeutic potential for treatment of pertussis is sphingosine-1-phosphate (S1P) signaling, which is mediated by G protein-coupled receptors (GPCR) whose signaling is inhibited by PT. S1P is a sphingolipid involved in regulation of vascular barrier integrity, immune cell trafficking, and several other cellular processes. Treatment with S1P receptor agonists increases pulmonary vascular barrier integrity and reduces lung inflammation in mouse models of LPS-induced acute lung injury and influenza virus infection. We have found that treatment of pertussis-infected infant mice with an S1P receptor agonist soon after bacterial inoculation significantly reduced lethality of this infection Therefore we will investigate the potentially beneficial effect of treatment with S1P receptor agonists on pertussis disease in infant mice, and determine whether PT inhibition of S1P signaling inhibits this beneficial effect. This study may identify novel therapeutic approaches to treatment of critical pertussis in infants.